title: Angiotensin-II type 1 receptor and NOX2 mediate TCF/LEF and CREB dependent WISP1 induction and cardiomyocyte hypertrophy.
abstract: Angiotensin-II (Ang-II) plays a key role in myocardial hypertrophy, remodeling and failure. We investigated whether Ang-II-induced cardiomyocyte hypertrophy is dependent on WNT1 inducible signaling pathway protein 1 (WISP1), a pro growth factor. Ang-II induced hypertrophy and WISP1 expression in neonatal rat cardiomyocytes (NRCM), effects that were significantly inhibited by pre-treatment with the AT1 antagonist losartan and by WISP1 knockdown. Further, Ang-II induced WISP1 was superoxide-dependent, and inhibited by DPI, an inhibitor of NADPH oxidases, and by knockdown of NOX2. AT1 was physically associated with NOX2 both in vitro and in vivo, and Ang-II increased this interaction in vivo. Ang-II induced WISP1 expression via superoxide/Akt/GSK3β/β-catenin/TCF/LEF and by Akt-dependent CREB activation. Further, Ang-II also activated CREB via superoxide-mediated p38 MAPK and ERK activation. Continuous infusion of Ang-II for 7days induced myocardial hypertrophy in rats, and was associated with increased Akt, p-Akt, p-p38 MAPK, p-ERK1/2, and WISP1 expression. These results demonstrate that Ang-II induced cardiomyocyte hypertrophy is mediated through AT1, NOX2 and the induction of WISP1, and may involve the direct interaction of AT1 with NOX2. Thus targeting both WISP1 and NOX2 may have a therapeutic potential in improving cardiomyocyte survival and growth following myocardial injury and remodeling. This article is part of a Special Issue entitled 'Possible Editorial'.
authors.affiliation: Research Service, Southeast Louisiana Veterans Health Care System, New Orleans, LA 70161, USA.
authors.forename: Prakashsrinivasan
authors.initials: P
authors.lastname: Shanmugam
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Valente
authors.forename: Sumanth D
authors.initials: SD
authors.lastname: Prabhu
authors.forename: Balachandar
authors.initials: B
authors.lastname: Venkatesan
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Patrice
authors.initials: P
authors.lastname: Delafontaine
authors.forename: Bysani
authors.initials: B
authors.lastname: Chandrasekar
mesh_terms: D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D055511:CCN Intercellular Signaling Proteins; D002312:Cardiomyopathy, Hypertrophic / Q000503:physiopathology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D051820:TCF Transcription Factors / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000378:metabolism / Q000494:pharmacology; D051176:beta Catenin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D055511:CCN Intercellular Signaling Proteins; C116396:CCN4 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D051820:TCF Transcription Factors; D014662:Vasoconstrictor Agents; D051176:beta Catenin; D013481:Superoxides; D000804:Angiotensin II; D019255:NADPH Oxidases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3